Typical anticancer agents presently available include, for example, alkylating agents, antimetabolites, molecular-targeted drugs, platinum drugs, plant-derived anticancer agents, anticancer antibiotics, BRM (biological response modifiers), cancer vaccines, cytokines, differentiation-inducing agents, monoclonal antibodies and hormonal anticancer agents.
Among the above anticancer agents, those that are biologicals have difficulties in large-scale production and cost along with a long period of time required for producing them. On the other hand, anticancer agents which are chemically synthesized using a rare metal have also difficulties in cost and large-scale production.
Recently, to solve the above problems, anticancer agents that can be chemically synthesized at a reasonable cost have been attracting attention. Among such anticancer agents, tyrosine kinase inhibitors, serving as a molecular-targeted drug, are expected to be useful as a therapeutic and/or prophylactic agent. Tyrosine kinase inhibitors inhibit the action of tyrosine kinases which promotes phosphorylation of tyrosine that is a specific amino acid contained in proteins (e.g., inhibiting autophosphorylation by tyrosine kinases), thereby suppressing the growth of cancer. Various tyrosine kinases are known, which include those of receptor type such as platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, epidermal growth factor (EGF) receptors and the like, as seen in Non-patent Literature 1. While these receptors are involved in cancer growth signals, HER2 is also known as a similar factor. Specifically, HER2 (human EGF receptor 2) gene is a gene for a transmembrane receptor glycoprotein. This receptor is also involved in tyrosine kinase activities. See Non-patent Literature 1. Further, epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) are involved in vascularization. These molecular-targeted drugs are also effective as an inhibitor for the activity of Abl tyrosine kinases, for example, as an inhibitor for the activity of Bcr-Abl kinase that is a protein causing chronic myelocytic leukemia (CML). Moreover, these molecular-targeted drugs are useful as prophylactic agents for preventing malignant transformation of cancer (e.g., acquisition of an infiltration ability and/or a metastatic ability by cancer cells) and canceration of cells (conversion of normal cells into cancer cells), which include, for example, a prophylactic agent for preventing transformation of hormone-dependent cancers such as one dependent on LH-RH (luteinizing hormone releasing hormone) into hormone-independent cancers, a prophylactic agent inducing apoptosis of cells to be transformed into cancer cells, and a prophylactic agent serving as an antioxidant for preventing transformation into cancer.
It is pointed out that tyrosine kinases are also involved in diseases other than cancer, which include, for example, diseases associated with inflammation or allergy (such as pollinosis, allergic rhinitis, allergic asthma, bronchial asthma, rhinitis, atopic dermatitis and the like), diabetes, and Alzheimer's disease. It is further pointed out that tyrosine kinases are associated with anticancer agents, anti-inflammatory agents, etc. While action mechanisms of tyrosine kinase inhibitors are still mostly unclear, some of those action mechanisms have recently been elucidated based on the chemical structure of them. These tyrosine kinase inhibitors include low molecular weight compounds and in such cases, large-scale production would be relatively easy. Accordingly, it is expected that many companies will enter this field of pharmaceutical products in the future.
However, presently available tyrosine kinase inhibitors have many problems. First, tyrosine kinase inhibitors presently on the market as a molecular-targeted drug show therapeutic performances which drastically vary depending upon patients. Second, drug resistance against those inhibitors can easily be developed.
Under the above circumstances, the present invention aims at providing a novel heterocyclic compound to be contained, particularly as an anticancer agent, in a pharmaceutical composition.